Journal Club

Not a bad news for fixed dose combination (FDC) enthusiasts! In a retrospective, longitudinal, cohort design study in the UK, it has been concluded that the safety risk outcomes do not differ between the concomitant use of ibuprofen and paracetamol as compared to the use of these drugs alone (De Vries F., Setakis E. and Van Staa T.-P. Concomitant use of ibuprofen and paracetamol and the risk of major clinical safety outcomes. Br J Clin Pharmacol 2010;70:429-38). The study was conducted on the medical records of 1.2 million patients (aged 18 years or over) stored at the General Practice Research Database (GPRD). Dose, duration and exposure patterns were taken into account. Using a number of statistical analyses, it was elucidated that the relative risks of upper gastrointestinal events, myocardial infarction, stroke, renal failure, congestive heart failure, intentional or accidental overdose, suicidal behavior and mortality were no different with the use of combination as compared to that of each drug alone. This combination, used in abundance in India, has generally been considered to be innocuous. However, omission of the hepatotoxicity from the list of outcomes immediately comes to the mind. More importantly, the superiority of the combination over either of the ingredients used alone remains to be established. 
 
Providing safe medicines is a complex task, particularly in case of children. The condition of children in terms of their access to safe medicines (or lack thereof) has been increasingly acknowledged. Several organizations (including WHO and UNICEF) have, therefore, launched a major campaign entitled “Make Medicines Child Size” with a view to improve the availability and access to safe, child specific medicines throughout the world. Against this background, the authors of a review article (Oshikoya KA, Senbanjo IO. Providing safe medicines for children in Nigeria: The impediments and remedies. Ann Afr Med 2010;9:203-12) have systematically analyzed the situation in Nigeria. Medicine related morbidity and mortality has been quite high in Nigeria where deaths due to counterfeit, fake medicines and unethical clinical trials have been brought to light. Authors have described the existing problems and their possible solutions in details. Lack of evidence-based practice, up-to-date information among prescribers and training and research in pediatric clinical pharmacology, inadequate training in undergraduate and postgraduate clinical pharmacology, irrational use of medicines, lack of pediatric focus in essential medicine list, lack of access to pediatric essential medicines (due to the non-availability of suitable formulations and lack of storage facilities, particularly in rural areas), lack of awareness of pediatric pharmacovigilance/pharmacoepidemiology and weak national drug policies are described to be some of the broad impediments. Suggested remedies include enhancing information to doctors, undertaking research and training in pediatric clinical pharmacology, review (and a possible correction) of undergraduate/postgraduate teaching of clinical pharmacology, encouraging the application of evidence-based medicine, strengthening national drug policies and education of parents. The problems that are listed may not be unique to Nigeria as they are prevalent in most of the developing world. Similarly, the solutions provided are also not unknown. The review, however, compiles a good number of problems and the remedial possibilities from which one can choose a possible area of action. 
 
A common experience gets the scientific approval! It has been detected that ingestion of caffeine causes several urinary effects (Lohsiriwat S, Hirunsai M, Chaiyaprasithi B. Effect of caffeine on bladder function in patients with overactive bladder symptoms. Urol Ann 2011;3:14-8). Authors carried out the investigation in 12 adult patients (9 females and 3 males) suffering from the symptoms of overactive bladder (OAB). Each subject was given 8 ml/kg of water with and without caffeine (4.5 mg/kg) at two separate sessions. A large number of urodynamic parameters were assessed through uroflowmetry (voided volume and time, time to maximum flow rate, peak/mean flow rate, etc.) and cystometry (first/normal or strong desire to void, various pressure parameters, etc.). It was observed that caffeine (1) causes diuresis, (2) increases the bladder sensitivity (the desire to void comes earlier), and (3) increases the flow rates (detrusor contractions become stronger at urgency and urine volume increases). These effects can promote early urgency and frequency of urination as well as nocturia. Therefore, symptoms in those with lower urinary tract disorders (such as OAB) may be aggravated and such individuals should avoid caffeine or caffeinated foodstuffs. A simple investigation with straightforward observations! Hopefully, the methodology employed can serve as a possible research tool in clinical pharmacology! 
 
Thanks to the massive instrumentation, many of us may wonder if the medicine as a profession has now transformed into a “medical technology”. Airing parallel views, author of an editorial (Kapoor MC. Evidence based medicine: Can everything be evident? Ann Card Anaesth 2011;14:3-5), feels that the “fashion” of evidence-based medicine (EBM) is likely to turn the medical practice into a "protocol-based recipe" that is least concerned about clinical techniques and individual innovations in patient care. Referring to about two dozen publications on this subject, the author traces the history of EBM to 1991 when the American College of Physicians (ACP) began a journal, “The ACP Journal Club”, and the year 1995 when the ACP and the BMJ Publishing Group collaborated to initiate the publication of another journal called “Evidence Based Medicine”. Cochrane Collaboration probably catalyzed the process further. Large randomized controlled clinical trials (RCT) and the meta-analyses became the backbone of EBM which further lead to the framing of appropriate guidelines. It is said that approximately 1000 guidelines are created annually, it is difficult to follow them and that the guidelines for framing the guidelines must also exist. Some of the failed (or flawed) guidelines (“Surviving Sepsis Guidelines-2004”, “Tight Glucose Control regime”, “Efficacy and anti-inflammatory effects of aprotinin”) are mentioned to bring home the point that a large amount of published research (that forms the very basis of EBM) may be untrustworthy. Several common errors in framing of RCTs and in selecting them for inclusion in meta-analyses have also been described (selection of only few clinical variables, less reliance on clinically observed data, differences in inclusion/exclusion criteria in the chosen RCTs, non-feasibility of RCTs in some clinical areas, differences in the quality of RCTs, their sample sizes and levels of significance, etc.). Publication biases, quality of reviewers and conflicts of interests (in developing the evidence-based guidelines) are described to be some other factors that may influence the studies. EBM may have come to stay and get stronger, but the observations described provide some food for thought for everyone sitting on either side of fence! 
 
Several functions have been ascribed to the clinical pharmacologists and now they are being called to act as health economists too! In a recently published informative review (Edlin R, Round J, Hulme C, McCabe C. Cost-effectiveness analysis and efficient use of the pharmaceutical budget; the key role of clinical pharmacologists. Br J Clin Pharmacol 2010;70:350-55), the authors opine that the clinical pharmacologists can play a significant role in delivering an efficient healthcare system by ensuring the meaningful allocation of budget using cost-effective analyses. This is particularly important in view of the shrinking healthcare budgets in developed countries and inadequate resources in developing economies. On the other hand, costs are always escalating, especially in case of newer therapies including the prescription drugs. Authors say that an efficient use of the available resources should be made, and for that matter, their most appropriate application would be to maximize the population health (rather than a single patient's interests). Thus, the least efficient health technologies should be removed and newer methods should be included in the healthcare system only if they are proved to be more efficient than the existing ones (Making the right disinvestment decision is as important as making the right investment decision). Readers are introduced to a number of pharmacoeconomic terms and their meaning (e.g. “Cost Effective Analysis”, “Quality Adjusted Life Year”, “Incremental Cost Effectiveness Ratios” and “Cost Effectiveness Threshold”, etc.) and adequate references have been given for the methods to calculate them. Those of us with an aptitude for economics may really want to go for it!

Rationale. Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated that these processes could be auto reactive.
Objectives. To ascertain if humoral autoimmunity could play a role in COPD pathogenesis. Methods: Circulating IgG autoantibodies were detected by immunofluorescence and immunoprecipitation. Immunohistochemistry and immunofluorescence were used to evaluate intrapulmonary IgG and complement (C3) deposition in human lung explants. Autoantibody pathogenicity was also investigated with an antibody-dependent cell-mediated cytotoxicity assay.
Measurements and Main Results. The prevalence of anti-HEp-2 epithelial cell autoantibodies in 47 smokers/former smokers with COPD (GOLD stages 1-4) was greater than among 8 subjects with a smoking history but normal spirometry and 21 healthy control subjects who had never smoked (68 vs. 13 vs. 10%, respectively; P < 0.0001). Antibodies against primary pulmonary epithelial cells were found in 12 of 12 patients with COPD versus 3 of 12 never-smoked control subjects (P < 0.001). Self-antigens immunoprecipitated from 34 of 35 (97%) of COPD plasmas (vs. 0/12 never-smoked controls). Antibodies against a particular 130-kD autoantigen (n = 7) were associated with decreased body mass index (23.2 +/− 2.1 vs. 29.5 +/− 1.0 kg/m(2), p = 0.007). Intrapulmonary immune complexes were present in six of six and C3 was seen in five of six COPD lung explants, unlike zero of six and one of six normals, respectively. Cytotoxicity of pulmonary epithelial cells by allogeneic mononuclear cells also increased 46% after incubation with COPD plasmas (n = 10), compared with identical treatments with eight normal specimens ( p = 0.03).
Conclusions. IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity, are prevalent in patients with COPD. Autoreactive adaptive immune responses may be important in the etiology of this disease.
Comments. The fact that it is only a subset of smokers that develop COPD points to the likely involvement of both adaptive and autoimmune responses contributing to the pathogenesis of COPD. The study largely looked at COPD patients that were currently non-smokers (38 of 47 subjects diagnosed with COPD were current non smokers) which is important since cigarette smoking has been reported to affect immunoglobulin and autoantibody production. The study consisted of two populations. In the first population auto-antibodies to HEp-2 cells and autoantibodies detected by immunoprecipitation were assessed. The second population consisted of lung tissue explants and cadeveric samples on which immune complexes and C3 were assessed. This renders the results somewhat confusing if not misleading. Nonetheless the findings point to the possibility that adaptive immunity and indeed auto-immune responses may be part of the explanation for the heterogeneity seen in patients with COPD. Background. The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking.
Results. IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], −61 to −20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, −37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories.
Conclusions. Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.
Comments. While it is generally accepted that COPD has a systemic inflammatory component it is also recognized that the nature of this response is likely complex and variable and indeed is influenced by a number of host factors. The Framingham Heart study provides a well characterized cohort of subjects to examine the relationships between various inflammatory markers in smokers and non smokers with COPD and/or presumably cardiovascular disease. While the associations between IL-6 and COPD have been previously reported, this study adds to the literature by demonstrating a fairly vigorous relationship between IL-6 and FEV-1. IL-6 is a primary cytokine regulator of a number of cytokines including CRP and fibrinogen and has been associated with a host of conditions including dyspnea, skeletal muscle weakness and pulmonary hypertension. There have now been studies to suggest that there is a systemic inflammatory component in asthma and that IL-6 levels in asthmatics may be comparable to those found in patients with COPD (See review of Higashimoto et al, above) . Hence IL-6 may be increased by several inflammatory lung diseases or at least airway diseases, and the eventual systemic inflammatory response downstream and consequent clinical manifestations are likely influenced by several other factors that require further elucidation. The Framingham data is useful to compare systemic inflammatory markers in asthmatics and COPD patients and to look for associations between these markers and the incidence of co-existing cardiovascular disease. Background. Treatment with systemic corticosteroids for exacerbations of COPD results in improvement in clinical outcomes. On hospitalization, corticosteroids are generally administered IV. It has not been established whether oral administration is equally effective. We conducted a study to demonstrate that therapy with oral prednisolone was not inferior to therapy with IV prednisolone using a double-blind, double-dummy design.

Oral or IV Prednisolone in the Treatment of COPD Exac
Methods. Patients hospitalized for an exacerbation of COPD were randomized to receive 5 days of therapy with prednisolone, 60 mg IV or orally. Treatment failure, the primary outcome, was defined as death, admission to the ICU, readmission to the ICU because of COPD, or the intensification of pharmacologic therapy during a 90-day follow-up period.
Conclusion. Therapy with oral prednisolone is not inferior to IV treatment in the first 90 days after starting therapy. We suggest that the oral route is preferable in the treatment of COPD exacerbations. Trial registration: Clinicaltrials.gov Identifier: NCT00311961.
Comments. While this study shows that there is no difference between treatment with iv steroids versus oral steroids in acute exacerbations (as has been shown in previous studies with asthmatics) it reports a fairly high treatment failure rate. This study from the Netherlands was carried out over two years at one institution and thus one may assume that the care was fairly similar for all participants. There were several exclusion criteria that cut the number of eligible subjects for randomization from 435 assessed to 210 being randomized, however, if anything this selected the less severe exacerbations as patients with evidence for pneumonia, co-morbid illness, heart failure, elevated CO2 or pH <7.2 were excluded. The greatest number of exclusions, however, were for patients already previously enrolled (102). The patient population were (on average) severe COPD patients (Gold Stage III) with FEV-1 approximately 38% predicted and average age around 70 years old and BMI around 26 Kg/m 2 . Patients were put on a steroid taper afterward starting at 30 mg and tapered off entirely within 11 days. Perhaps this study's most instructive data was that 5 days of iv or oral prednisone at 60 mg is too short a course of high dose steroids before starting taper. It would be helpful to have a similar study that compares 5 days versus perhaps 2 weeks before starting taper with perhaps the iv group switching to oral after hospital discharge to make it a "real world" study. Considering the high costs associated with treatment of exacerbations this remains a controversial yet important clinical question that remains unanswered.